Abstract
The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-α and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDγc (null) mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling.
© 2015 by The American Society of Hematology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / pathology
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Cell Line, Tumor
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Coculture Techniques
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Gene Expression Regulation, Leukemic*
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Humans
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Immune Tolerance
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Interleukin-6 / genetics
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Interleukin-6 / immunology*
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Janus Kinase 1 / genetics
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Janus Kinase 1 / immunology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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MicroRNAs / genetics
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MicroRNAs / immunology*
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Oligonucleotides / pharmacology
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RNA, Long Noncoding
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology
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Signal Transduction
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Stromal Cells / drug effects
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Stromal Cells / immunology*
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Stromal Cells / pathology
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Toll-Like Receptor 7 / antagonists & inhibitors
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / immunology
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Tumor Microenvironment
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies, Neutralizing
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IL6 protein, human
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Interleukin-6
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MIR17HG, human
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MIRN17 microRNA, human
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MIRN19 microRNA, human
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MicroRNAs
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Oligonucleotides
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RNA, Long Noncoding
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RNA, Messenger
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STAT3 Transcription Factor
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STAT3 protein, human
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TLR7 protein, human
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Toll-Like Receptor 7
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Tumor Necrosis Factor-alpha
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Janus Kinase 1